tbuckley/cabot-search huggingface dataset:
Integrative Analysis of a Large Real-World Cohort of Small Cell Lung Cancer Identifies Distinct Genetic Subtypes and Insights into Histologic Transformation
Authors: Smruthy Sivakumar, Jay A. Moore, Meagan Montesion, Radwa Sharaf, Douglas I. Lin, Caterina I. Colón, Zoe Fleishmann, Ericka M. Ebot, Justin Y. Newberg, Jennifer M. Mills, Priti S. Hegde, Quintin Pan, Afshin Dowlati, Garrett M. Frampton, Julien Sage, Christine M. Lovly
Journal: Cancer Discovery (2023)

Abstract Small cell lung cancer (SCLC) is a recalcitrant neuroendocrine carcinoma with dismal survival outcomes. A major barrier in the field has been the relative paucity of human tumors studied. Here we provide an integrated analysis of 3,600 “real-world” SCLC cases. This large cohort allowed us to identify new recurrent alterations and genetic subtypes, including STK11-mutant tumors (1.7%) and TP53/RB1 wild-type tumors (5.5%), as well as rare cases that were human papillomavirus–positive. In our cohort, gene amplifications on 4q12 are associated with increased overall survival, whereas CCNE1 amplification is associated with decreased overall survival. We also identify more frequent alterations in the PTEN pathway in brain metastases. Finally, profiling cases of SCLC containing oncogenic drivers typically associated with NSCLC demonstrates that SCLC transformation may occur across multiple distinct molecular cohorts of NSCLC. These novel and unsuspected genetic features of SCLC may help personalize treatment approaches for this fatal form of cancer. Significance: Minimal changes in therapy and survival outcomes have occurred in SCLC for the past four decades. The identification of new genetic subtypes and novel recurrent mutations as well as an improved understanding of the mechanisms of transformation to SCLC from NSCLC may guide the development of personalized therapies for subsets of patients with SCLC. This article is highlighted in the In This Issue feature, p. 1501
Cell membrane derived liposomes loaded with DNase I target neutrophil extracellular traps which inhibits colorectal cancer liver metastases
Authors: Zhaozhong Wang, Chen Chen, Chongdeng Shi, Xiaotian Zhao, Lin Gao, Feiyue Guo, Maosen Han, Zhenmei Yang, Jing Zhang, Chunwei Tang, Cai Zhang, Ying Liu, Peng Sun, Xinyi Jiang
Journal: Journal of Controlled Release (2023)
A Transcriptome-Based Precision Oncology Platform for Patient–Therapy Alignment in a Diverse Set of Treatment-Resistant Malignancies
Authors: Prabhjot S. Mundi, Filemon S. Dela Cruz, Adina Grunn, Daniel Diolaiti, Audrey Mauguen, Allison R. Rainey, Kristina Guillan, Armaan Siddiquee, Daoqi You, Ronald Realubit, Charles Karan, Michael V. Ortiz, Eugene F. Douglass, Melissa Accordino, Suzanne Mistretta, Frances Brogan, Jeffrey N. Bruce, Cristina I. Caescu, Richard D. Carvajal, Katherine D. Crew, Guarionex Decastro, Mark Heaney, Brian S. Henick, Dawn L. Hershman, June Y. Hou, Fabio M. Iwamoto, Joseph G. Jurcic, Ravi P. Kiran, Michael D. Kluger, Teri Kreisl, Nicole Lamanna, Andrew B. Lassman, Emerson A. Lim, Gulam A. Manji, Guy M. McKhann, James M. McKiernan, Alfred I. Neugut, Kenneth P. Olive, Todd Rosenblat, Gary K. Schwartz, Catherine A. Shu, Michael B. Sisti, Ana Tergas, Reena M. Vattakalam, Mary Welch, Sven Wenske, Jason D. Wright, Peter Canoll, Hanina Hibshoosh, Kevin Kalinsky, Mahalaxmi Aburi, Peter A. Sims, Mariano J. Alvarez, Andrew L. Kung, Andrea Califano
Journal: Cancer Discovery (2023)

Abstract Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study. Significance: Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials. This article is highlighted in the In This Issue feature, p. 1275
Presurgery Plus Postsurgery Immunotherapy Ups Survival in NSCLC
Journal: Cancer Discovery (2023)

Adding the PD-L1 inhibitor durvalumab to chemotherapy before and after surgery led to improved pathological complete response rates and event-free survival in patients with untreated, operable non-small cell lung cancer, according to interim results from the AEGEAN trial. Researchers noted that administering immunotherapy prior to surgery may help in developing more tailored adjuvant treatments based on patients' responses and tumor characteristics.
mRNA Vaccine Slows Melanoma Recurrence
Journal: Cancer Discovery (2023)

Abstract Findings from the phase IIb KEYNOTE-942 trial indicate that the investigational vaccine mRNA-4157/V940 plus pembrolizumab is a potential adjuvant therapy for high-risk melanoma. Following surgery, patients who received the combination experienced a significant reduction in disease recurrence risk, compared with those given just PD-1 inhibitor.
PPRX-1701, a nanoparticle formulation of 6′-bromoindirubin acetoxime, improves delivery and shows efficacy in preclinical GBM models
Authors: Mykola Zdioruk, Jorge-Luis Jimenez-Macias, Michal Oskar Nowicki, Katherine E. Manz, Kurt D. Pennell, Marilin S. Koch, Tomer Finkelberg, Bin Wu, Paul Boucher, Yuji Takeda, Weiyi Li, Raziye Piranlioglu, Alexander L. Ling, E. Antonio Chiocca, Sean E. Lawler
Journal: Cell Reports Medicine (2023)

Derivatives of the Chinese traditional medicine indirubin have shown potential for the treatment of cancer through a range of mechanisms. This study investigates the impact of 6′-bromoindirubin-3′-acetoxime (BiA) on immunosuppressive mechanisms in glioblastoma (GBM) and evaluates the efficacy of a BiA nanoparticle formulation, PPRX-1701, in immunocompetent mouse GBM models. Transcriptomic studies reveal that BiA downregulates immune-related genes, including indoleamine 2,3-dioxygenase 1 (IDO1), a critical enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway in tumor cells. BiA blocks interferon-γ (IFNγ)-induced IDO1 protein expression in vitro and enhances T cell-mediated tumor cell killing in GBM stem-like cell co-culture models. PPRX-1701 reaches intracranial murine GBM and significantly improves survival in immunocompetent GBM models in vivo. Our results indicate that BiA improves survival in murine GBM models via effects on important immunotherapeutic targets in GBM and that it can be delivered efficiently via PPRX-1701, a nanoparticle injectable formulation of BiA.
Photothermal‐Responsive Intelligent Hybrid of Hierarchical Carbon Nanocages Encapsulated by Metal−Organic Hydrogels for Sensitized Photothermal Therapy
Authors: Fang Wang, Baoxing Wang, Xiang Xu, Xiaoliang Wang, Pei Jiang, Zheng Hu, Xizhang Wang, Jianping Lei
Journal: Advanced Healthcare Materials (2023)

Abstract Hierarchical carbon nanocages as emerging nanomaterials have a great potential for photothermal therapy due to their unique porous structure, high specific surface area, and excellent photothermal property. Herein, a hierarchical nitrogen‐doped carbon nanocage (hNCNC) is introduced as a second near‐infrared photothermal agent, and then functionalizes it with metal‐organic hydrogel (MOG) to form a thermal‐responsive switch for sensitized photothermal therapy. Upon 1064 nm light irradiation, the hNCNCs exhibit a remarkable photothermal conversion efficiency of 65.9% owing to a high near‐infrared extinction coefficient. Meanwhile, due to the hierarchical structure, hNCNCs show 60.2% (wt./wt.) loading efficiency of quercetin, a heat shock protein (Hsp70) inhibitor. Through thermal‐driven dry‐gel transformation, the coating MOGs intelligently release the encapsulated quercetin for sensitizing cancer cells to heat. Based on the synergistic effect of hyperthermia elevation and thermal‐driven drug release, the dual thermal utilization platform achieves effective photothermal tumor ablation in vivo under low concentration of hNCNCs and mild irradiation, which provides a new diagram of intelligent responsive photothermal agents for enhanced photothermal therapy.
Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth
Authors: Youchao Dai, Chuanzhi Zhu, Wei Xiao, Kaisong Huang, Xin Wang, Chenyan Shi, Dachuan Lin, Huihua Zhang, Xiaoqian Liu, Bin Peng, Yi Gao, Cui Hua Liu, Baoxue Ge, Stefan H.E. Kaufmann, Carl G. Feng, Xinchun Chen, Yi Cai
Journal: Journal of Clinical Investigation (2023)

Ferritin, a key regulator of iron homeostasis in macrophages, has been reported to confer host defenses against Mycobacterium tuberculosis (Mtb) infection. Nuclear receptor coactivator 4 (NCOA4) was recently identified as a cargo receptor in ferritin degradation. Here, we show that Mtb infection enhanced NCOA4-mediated ferritin degradation in macrophages, which in turn increased the bioavailability of iron to intracellular Mtb and therefore promoted bacterial growth. Of clinical relevance, the upregulation of FTH1 in macrophages was associated with tuberculosis (TB) disease progression in humans. Mechanistically, Mtb infection enhanced NCOA4-mediated ferritin degradation through p38/AKT1- and TRIM21-mediated proteasomal degradation of HERC2, an E3 ligase of NCOA4. Finally, we confirmed that NCOA4 deficiency in myeloid cells expedites the clearance of Mtb infection in a murine model. Together, our findings revealed a strategy by which Mtb hijacks host ferritin metabolism for its own intracellular survival. Therefore, this represents a potential target for host-directed therapy against tuberculosis.
T cells heal bone fractures with help from the gut microbiome
Authors: Rajeev Aurora, Matthew J. Silva
Journal: Journal of Clinical Investigation (2023)

Immune cells play an important functional role in bone fracture healing. Fracture repair is a well-choreographed process that takes approximately 21 days in healthy mice. While the process is complex, conceptually it can be divided into four overlapping stages: inflammation, cartilaginous callus formation, bony callus formation, and remodeling. T cells play a key role in both the cartilaginous and bony callus phases by producing IL-17A. In this issue of the JCI, Dar et al. showed that T cells were recruited from the gut, where the gut microbiota determined the pool of T cells that expressed IL-17A. Treatment with antibiotics and dysbiosis reduced the expansion of IL-17–expressing CD4+ T cells (Th17) and impaired callus formation. These findings demonstrate crosstalk among the gut microbiota, the adaptive immune system, and bone that has clinical implications for fracture healing.
Hepatocyte SREBP signaling mediates clock communication within the liver
Authors: Dongyin Guan, Hosung Bae, Dishu Zhou, Ying Chen, Chunjie Jiang, Cam Mong La, Yang Xiao, Kun Zhu, Wenxiang Hu, Trang Minh Trinh, Panpan Liu, Ying Xiong, Bishuang Cai, Cholsoon Jang, Mitchell A. Lazar
Journal: Journal of Clinical Investigation (2023)

Rhythmic intraorgan communication coordinates environmental signals and the cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific KO of core components of the molecular clock Rev-erbα and -β (Reverb-hDKO) alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in nonparenchymal cells (NPCs) of the liver. Here, we report that in fatty liver caused by diet-induced obesity (DIO), hepatocyte SREBP cleavage–activating protein (SCAP) was required for Reverb-hDKO–induced diurnal rhythmic remodeling and epigenomic reprogramming in liver macrophages (LMs). Integrative analyses of isolated hepatocytes and LMs revealed that SCAP-dependent lipidomic changes in REV-ERB–depleted hepatocytes led to the enhancement of LM metabolic rhythms. Hepatocytic loss of REV-ERBα and β (REV-ERBs) also attenuated LM rhythms via SCAP-independent polypeptide secretion. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in fatty liver disease caused by DIO.
Peeling the onion: another layer in the regulation of insulin secretion
Authors: Kristie I. Aamodt, Alvin C. Powers
Journal: Journal of Clinical Investigation (2023)

Insulin secretion by pancreatic β cells is a dynamic and highly regulated process due to the central importance of insulin in enabling efficient utilization and storage of glucose. Multiple regulatory layers enable β cells to adapt to acute changes in nutrient availability as well as chronic changes in metabolic demand. While epigenetic factors have been well established as regulators of chronic β cell adaptations to insulin resistance, their role in acute adaptations in response to nutrient stimulation has been relatively unexplored. In this issue of the JCI, Wortham et al. report that short-term dynamic changes in histone modifications regulated insulin secretion and acute β cell adaptations in response to fasting and feeding cycles. These findings highlight the importance of investigating whether other epigenetic mechanisms may contribute to acute physiologic adaptations in β cells.
Viewing both sides of the coin for infectious disease diagnosis
Authors: Fiona R. Strouts, Linda B. McAllister, Ephraim L. Tsalik
Journal: Journal of Clinical Investigation (2023)

Optimal management of lower respiratory tract infection relies on distinguishing infectious from noninfectious etiologies and identifying the microbiologic cause if applicable. This process is complicated by overlapping clinical symptoms and the colonizing lung microbiota. In a recent issue of the JCI, Mick, Tsitsiklis, and colleagues apply RNA-Seq to tracheal aspirates from critically ill children and demonstrate how integration of the host response with microbial identification results in a harmonious and accurate diagnostic classifier. Though promising, there are numerous barriers to realizing a combined host and pathogen diagnostic.
Does the SARS-CoV-2 spike really have an Achilles heel?
Authors: Shiv Pillai
Journal: Journal of Clinical Investigation (2023)

The continued emergence of SARS-CoV-2 variants and waning vaccine immunity are some of the factors that drive the continuing search for more effective treatment and prevention options for COVID-19. In this issue of the JCI, Changrob, et al. describe an anti-SARS-CoV-2 spike antibody, isolated from a patient, that targets a vulnerable site on the spike protein receptor binding domain when it adopts a configuration called the “up” conformation. This antibody cross-neutralized all variants studied, including recent Omicron subvariants, and was protective against multiple variants in a hamster model. These results are of interest when considering the next generation of prophylactic and therapeutic antibodies for COVID-19, but they may also shape future approaches to vaccination against SARS-CoV-2.
Deconstructing cellular senescence in bone and beyond
Authors: Lorenz C. Hofbauer, Franziska Lademann, Martina Rauner
Journal: Journal of Clinical Investigation (2023)

Osteocytes are specialized bone cells that orchestrate skeletal remodeling. Senescent osteocytes are characterized by an activation of cyclin-dependent kinase inhibitor p16Ink4a and have been implicated in the pathogenesis of several bone loss disorders. In this issue of the JCI, Farr et al. have now shown that systemic removal of senescent cells (termed senolysis) prevented age-related bone loss at the spine and femur and mitigated bone marrow adiposity through a robust effect on osteoblasts and osteoclasts, whereas cell-specific senolysis in osteocytes alone was only partially effective. Surprisingly, transplantation of senescent fibroblasts into the peritoneum of young mice caused host osteocyte senescence associated with bone loss. This refined concept of osteocyte senescence and the effects of remote senolysis may help to develop improved senolytic strategies against multisystem aging in bone and beyond.
Lysosomal lipid peroxidation mediates immunogenic cell death
Authors: Pravin Phadatare, Jayanta Debnath
Journal: Journal of Clinical Investigation (2023)

Cancer cells rely on lysosome-dependent degradation to recycle nutrients that serve their energetic and biosynthetic needs. Despite great interest in repurposing the antimalarial hydroxychloroquine as a lysosomal inhibitor in clinical oncology trials, the mechanisms by which hydroxychloroquine and other lysosomal inhibitors induce tumor-cell cytotoxicity remain unclear. In this issue of the JCI, Bhardwaj et al. demonstrate that DC661, a dimeric form of chloroquine that inhibits palmitoyl-protein thioesterase 1 (PPT1), promoted lysosomal lipid peroxidation, resulting in lysosomal membrane permeabilization and tumor cell death. Remarkably, this lysosomal cell death pathway elicited cell-intrinsic immunogenicity and promoted T lymphocyte–mediated tumor cell clearance. The findings provide the mechanistic foundation for the potential combined use of immunotherapy and lysosomal inhibition in clinical trials.
Predicting liposome formulations by the integrated machine learning and molecular modeling approaches
Authors: Run Han, Zhuyifan Ye, Yunsen Zhang, Yaxin Cheng, Ying Zheng, Defang Ouyang
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Liposome is one of the most widely used carriers for drug delivery because of the great biocompatibility and biodegradability. Due to the complex formulation components and preparation process, formulation screening mostly relies on trial-and-error process with low efficiency. Here liposome formulation prediction models have been built by machine learning (ML) approaches. The important parameters of liposomes, including size, polydispersity index (PDI), zeta potential and encapsulation, are predicted individually by optimal ML algorithm, while the formulation features are also ranked to provide important guidance for formulation design. The analysis of key parameter reveals that drug molecules with logS [-3, -6], molecular complexity [500, 1000] and XLogP3 (≥2) are priority for preparing liposome with higher encapsulation. In addition, naproxen (NAP) and palmatine HCl (PAL) represented the insoluble and water-soluble molecules are prepared as liposome formulations to validate prediction ability. The consistency between predicted and experimental value verifies the satisfied accuracy of ML models. As the drug properties are critical for liposome particles, the molecular interactions and dynamics of NAP and PAL liposome are further investigated by coarse-grained molecular dynamics simulations. The modeling structure reveals that NAP molecules could distribute into lipid layer, while most PAL molecules aggregate in the inner aqueous phase of liposome. The completely different physical state of NAP and PAL confirms the importance of drug properties for liposome formulations. In summary, the general prediction models are built to predict liposome formulations, and the impacts of key factors are analyzed by combing ML with molecular modeling. The availability and rationality of these intelligent prediction systems have been proved in this study, which could be applied for liposome formulation development in the future.
All-cause and cause-specific mortality among people with and without intellectual disabilities during the COVID-19 pandemic in the Netherlands: a population-based cohort study
Authors: Maarten Cuypers, Monique C J Koks-Leensen, Bianca W M Schalk, Esther J Bakker-van Gijssel, Geraline L Leusink, Jenneken Naaldenberg
Journal: The Lancet Public Health (2023)
Hemolysis and Changes in Erythrocyte Membrane Lipids
Authors: Stephen B. Shohet
Journal: New England Journal of Medicine (1972)

Extracellular Disorders Influencing HemolysisThe major extracellular abnormalities are those in serum lipoproteins that induce secondary changes in the red cells by modifying the equilibrium of the passive exchange of lipids between the plasma and the erythrocytes (reactions 1 and 3, Fig. 3).Hepatic DiseaseIn both obstructive and hepatocellular liver disease, red cells may become laden with excess cholesterol and, to a lesser extent, excess phospholipid.90 , 91 They then assume a "targeted" morphology on air-dried blood smears owing to the consequent excess of membrane surface area. Using the osmotic fragility as an indirect measure of surface area, Cooper has calculated . . .
ACC/AHA Guidelines for Exercise Testing: Executive Summary
Authors: Raymond J. Gibbons, Gary J. Balady, John W. Beasley, None FAAFP, J. Timothy Bricker, Wolf F. C. Duvernoy, Victor F. Froelicher, Daniel B. Mark, Thomas H. Marwick, Ben D. McCallister, Paul Davis Thompson, None FACSM, William L. Winters, Frank G. Yanowitz
Journal: Circulation (1997)
Plasma Renin Activity in Primary Aldosteronism
Authors: Jerome W. Conn
Journal: JAMA (1964)

DETAILED STUDIES, in the preceding communication (p 213), on three subsequently proved cases of primary aldosteronism indicate conclusively that in the presence of an aldosterone-secreting tumor, plasma renin activity is suppressed to zero, and it cannot be increased above zero even after many days of severe sodium deprivation. Using the same method of extraction and assay for renin activity, a normal range was established from 18 healthy subjects studied under various conditions. In all cases renin activity of various intensities was easily measurable, and the values tripled upon restriction of sodium for 72 hours.<sup>2</sup> The suppression of renal release of renin in primary aldosteronism is not due to a high blood level of aldosterone, per se, but rather to the increase in intravascular volume and pressure which is known to be associated with it.<sup>3,4</sup>The increase in "stretch"<sup>5</sup>at the baroreceptor site (juxtaglomerular cells) in the afferent
Button Battery Ingestions
Authors: Toby L. Litovitz
Journal: JAMA (1983)

A retrospective analysis of 56 button (miniature) battery ingestions was conducted. This represents the largest series in the literature studying this problem. Impaction of these foreign bodies, most frequently in the esophagus (five cases), was a uniform predictor of severe morbidity. In the remaining 51 cases, the battery traversed the esophagus without incident; only four of these ingestions produced symptoms, and there was only one case with any severe complications. In 33 asymptomatic patients, the battery passed spontaneously through the gastrointestinal tract. Fourteen patients underwent endoscopic or operative procedures or both despite the absence of symptoms. Unanticipated mucosal erosions were noted in seven of these patients, although no symptoms or sequelae developed. Initial chest roentgenogram and observation for symptoms will detect ingestors at risk of complications. Operative or endoscopic intervention should be withheld in the absence of these clinical indicators. Button batteries can routinely be allowed to pass spontaneously. (<i>JAMA</i>1983;249:2495-2500)